Research Papers:

eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study

Andrea Casadei Gardini _, Giorgia Marisi, Luca Faloppi, Emanuela Scarpi, Francesco Giuseppe Foschi, Massimo Iavarone, Gianfranco Lauletta, Jody Corbelli, Martina Valgiusti, Floriana Facchetti, Cristina della Corte, Luca Maria Neri, Stefano Tamberi, Stefano Cascinu, Mario Scartozzi, Dino Amadori, Oriana Nanni, Elena Tenti, Paola Ulivi and Giovanni Luca Frassineti

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Oncotarget. 2016; 7:27988-27999. https://doi.org/10.18632/oncotarget.8569

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Andrea Casadei Gardini1,*, Giorgia Marisi2,*, Luca Faloppi3, Emanuela Scarpi4, Francesco Giuseppe Foschi5, Massimo Iavarone6, Gianfranco Lauletta7, Jody Corbelli8, Martina Valgiusti1, Floriana Facchetti6, Cristina della Corte6, Luca Maria Neri9, Stefano Tamberi8, Stefano Cascinu3, Mario Scartozzi10, Dino Amadori1, Oriana Nanni4, Elena Tenti1, Paola Ulivi2,**, Giovanni Luca Frassineti1,**

1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

2Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

3Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy

4Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

5DPT Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy

6A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy

7Department of Biomedical Sciences and Human Oncology, Internal Medicine “G. Baccelli”, University of Bari “A. Moro”, Bari, Italy

8Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy

9Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

10Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy

*These first authors contributed equally to this work

**These authors have contributed equally to this work

Correspondence to:

Giorgia Marisi, e-mail: [email protected]

Keywords: hepatocellular carcinoma, endothelial nitric oxide synthase, single nucleotide polymorphisms, biomarkers, angiogenesis

Received: February 08, 2016    Accepted: March 28, 2016    Published: April 4, 2016


Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs.18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.

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PII: 8569